US6016367A - Method for the acquisition of images by confocal - Google Patents

Method for the acquisition of images by confocal Download PDF

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Publication number
US6016367A
US6016367A US08/935,298 US93529897A US6016367A US 6016367 A US6016367 A US 6016367A US 93529897 A US93529897 A US 93529897A US 6016367 A US6016367 A US 6016367A
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image
confocal
max
light
grid
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US08/935,298
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Pier Alberto Benedetti
Valtere Evangelista
Dante Guidarini
Stefano Vestri
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Consiglio Nazionale delle Richerche CNR
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Consiglio Nazionale delle Richerche CNR
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Assigned to CONSIGLIO NAZIONALE DELLE RICERCHE reassignment CONSIGLIO NAZIONALE DELLE RICERCHE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BENEDETTI, PIER ALBERTO, EVANGELISTA, VALTERE, GUIDARINI, DANTE, VESTRI, STEFANO
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    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/0004—Microscopes specially adapted for specific applications
    • G02B21/002—Scanning microscopes
    • G02B21/0024—Confocal scanning microscopes (CSOMs) or confocal "macroscopes"; Accessories which are not restricted to use with CSOMs, e.g. sample holders
    • G02B21/0036—Scanning details, e.g. scanning stages
    • G02B21/004—Scanning details, e.g. scanning stages fixed arrays, e.g. switchable aperture arrays
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/0004—Microscopes specially adapted for specific applications
    • G02B21/002—Scanning microscopes
    • G02B21/0024—Confocal scanning microscopes (CSOMs) or confocal "macroscopes"; Accessories which are not restricted to use with CSOMs, e.g. sample holders
    • G02B21/0052—Optical details of the image generation
    • G02B21/0056—Optical details of the image generation based on optical coherence, e.g. phase-contrast arrangements, interference arrangements
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/0004—Microscopes specially adapted for specific applications
    • G02B21/002—Scanning microscopes
    • G02B21/0024—Confocal scanning microscopes (CSOMs) or confocal "macroscopes"; Accessories which are not restricted to use with CSOMs, e.g. sample holders
    • G02B21/0052—Optical details of the image generation
    • G02B21/0076—Optical details of the image generation arrangements using fluorescence or luminescence
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/0004—Microscopes specially adapted for specific applications
    • G02B21/002—Scanning microscopes
    • G02B21/0024—Confocal scanning microscopes (CSOMs) or confocal "macroscopes"; Accessories which are not restricted to use with CSOMs, e.g. sample holders
    • G02B21/008—Details of detection or image processing, including general computer control
    • G—PHYSICS
    • G06—COMPUTING OR CALCULATING; COUNTING
    • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
    • G06T5/00—Image enhancement or restoration
    • G06T5/50—Image enhancement or restoration using two or more images, e.g. averaging or subtraction

Definitions

  • the present invention relates to a method for the acquisition of images by means of confocal microscopy.
  • the present invention relates to a method for the confocal images acquisition in optical systems for the analytical microscopy and in other optical systems with a relatively high numerical aperture involving the electronic images acquisition.
  • the objects to be analysed can be absorbing (transmission), reflecting or fluorescent, and the optical arrangements can therefore vary among those for the analysis under transmitted or reflected light or under fluorescence.
  • Confocal techniques are very effective when the relatively thick structure(s) under observation, of which a tridimensional structure must be obtained, are immersed in a relatively transparent and thin material.
  • the object of interest is illuminated by means of a group of light beams concentrated on positions belonging to a focus plane and arranged on said plane according to a ordered bidimensional grid.
  • the complete lighting of the field under examination is obtained by the systematical displacement according two coordinates of the grid so as to cover all spaces among the focused light points originated by the grid.
  • the acquisition of the set of partial images, obtained in correspondence to each position of the illumination grid in the focus plane is first carried out by means of an electronic image sensing device. In this way, a values distribution depending on the grid position is obtained for each image element.
  • confocal images are obtained by analysing the above mentioned values distribution by using statistical-mathematical procedures with an increasing degree of complexity and accuracy, of the type described below.
  • Max(x) has confocal characteristics as mainly contains the signal coming from the most luminous and in focus areas, even if a part of the signal coming from the less luminous areas is contained, as they are relatively out of focus or sideways displaced with respect to the grid positions.
  • a second image, Min(x), constituted by the minima of luminosity among the corresponding elements of each captured image is then calculated.
  • the second image mainly contains the signal coming from the less luminous areas in so far as they are less in focus or displaced sideways, while it tends to exclude the signal coming from the most luminous areas.
  • the image of the luminosity maxima contains both the lighting due to the part in focus of the object under examination, and that of the less luminous part, not in focus, while the minima image tends to be affected only by the less luminous part and out of focus of them.
  • an image with enhanced confocal characteristics i.e. a more accurate optical section, is obtained by calculating the difference between the maxima image and the minima image.
  • a further improvement of the invention fit for avoiding the above shift of the zero level and even to increase the spatial resolution, consist in calculating a new image, Med(x), formed by the median values or by the average values among the corresponding elements of each of the captured images, and in carrying out a mathematical processing of the signal that can be represented by the formula.
  • K is a gain factor correlated to the shape of the lighting areas.
  • FIG. 1 is a general exemplifying diagram of a confocal microscopy system
  • FIG. 2 is a wave form diagram of the signals of a system of light reflection microscopy of the image on a generic line of a matrix sensor as a function of the displacement of the illumination grid along an axis;
  • FIG. 3 is a diagram similar to that of FIG. 2 in which the result of the "maximum minus minimum” operation is shown;
  • FIG. 4 is a diagram similar to those of FIGS. 2 and 3, in which the operation K (Max+Min-2Med) is executed;
  • FIG. 5 is a possible data processing block flow diagram for the system of the invention.
  • FIG. 6, particulars a) , b) , c) , d) , e) , f) , shows various images from the initial condition to the final one in an image processing method as shown in FIG. 4.
  • a light source 10 cooperates with a collimating lens 11, the output light beam of which passes through a hole matrix diaphragm 12 or equivalent device which is displaced according two coordinate axes x, y by means of motors, not shown, preferably by step motors.
  • the structure formed by said hole matrix diaphragm can be replaced by a xy matrix scanning device formed by a liquid crystal light valve optoelectronic device and without moving mechanical parts.
  • the light passing through hole matrix diaphragm 12 meets a beam divider 15. A part of the light crossing beam divider 15 is focused on a specimen 16 by means of a lens 17.
  • the part of the light reflected at left of beam divider 15 is captured by a light trap 19 as well-known in these optical arrangements to eliminate back scattered disturbing light.
  • the light returning from specimen 16 is directed to an image photoelectric sensor 18 such as a bidimensional CCD sensor.
  • image photoelectric sensor 18 such as a bidimensional CCD sensor. The operation of such an optical arrangement is well-known to a person skilled in the art and a detailed description is omitted.
  • the optical system shown in FIG. 1 is relevant to the analysis by reflection of a specimen and an electromechanical system for the displacement of the hole matrix diaphragm 12 is provided.
  • Different optical systems relevant to the specimen analysis by transmission and/or by fluorescence are included in the scope of the invention.
  • optoelectronic means to carry out the scanning of the hole matrix diaphragm 12 or to perform in a different way the function of the illumination grid. This can be done, for example, by means of spatial light modulators without moving parts of the type disclosed by Fairfield and Vaytek in VIRTUAL MICROSCOPE, European Microscopy, May 1996.
  • the same operation can also be carried out by using DMD (Digital Micromirror Device) devices as described by J. M. Younse in "MIRRORS ON A CHIP", IEEE Spectrum, November 1993.
  • DMD Digital Micromirror Device
  • FIGS. 2, 3 and 4 relate to a single scanning line through a generic specimen and are equal to those which could correspond to linear image sensor or to a generic scanning line passing through the specimen of a bidimensional image sensor. It has to be pointed out that the use of an image sensor of a linear or bidimensional type is given only by way of example of a commonly used optoelectronic sensor, and it is understood that the use of sensors of different type is included in the scope of the invention.
  • the horizontal axis represents the space that the specimen crosses, while the vertical axis represents relative intensity (or density) of the signal on an arbitrary scale in the various figures.
  • Line 100 indicates the confocal illumination process of the specimen carried out by the displacement, for example, along the x-coordinate of the hole matrix diaphragm or spatial modulator 12, as shown in FIG. 1.
  • peaks 101 are the illumination peaks of the specimen in a generic position m of diaphragm 12.
  • Peaks 102, 103 are the displacement of peaks 101 in the positions m+1, m+2 respectively controlled by the motors that perform the displacement of diaphragm 12.
  • Line 105 shows the wave form diagram of the optical density (opacity) of a generic specimen, the path comprising portions 106, 107 having null optical density (perfect transparency) of the specimen and portions 108, 109, 110, 111, 112 having an intermediate optical density between the null density (106, 107) and the maximum one 113.
  • Line 114 shows the output of a detector such as a CCD photodetector (indicated at 18 in FIG. 1), said output being formed by an envelope of peaks corresponding to the peaks of line 100 spatially modulated by the optical density of the specimen shown in line 105.
  • a detector such as a CCD photodetector (indicated at 18 in FIG. 1)
  • envelope 115 of line 116 is obtained representing a true reproduction of the specimen image details exemplified at line 105.
  • FIG. 3 there is shown the signal processing according to the invention in which an unwanted background signal, of a systematic type and produced by the presence of something causing scattering in the specimen not being part of the interested image of the same, is removed.
  • Lines 100 and 105 of FIG. 3 have the same meaning as the corresponding one of FIG. 2.
  • an unwanted background signal or systematic noise indicated at line 120 is associated to curve 105 representing the specimen.
  • the output signal would be that indicated at line 116' constituted by an envelope practically formed by adding the specimen signal (line 105) to the unwanted signal (line 120).
  • Final signal 122 can be represented as A(Max-Min) - where A is a proportionality constant that can be taken equal to 1.
  • FIG. 4 A variation of the processing method according to the invention, directed to remove (or, at least, significantly reduce) systematic and/or casual noises and the like is shown in FIG. 4.
  • Line 130 of FIG. 4 shows the illumination (likewise line 100 of FIG. 2).
  • Line 131 shows the specimen density (likewise line 105 of FIGS. 2 and 3).
  • Line 132 is the theoretical image of the specimen taken alone.
  • Line 133 shows the path of the possible systematic+casual noise.
  • Line 134 shows the photoelectric sensor output signal, curve 135 the envelope of the "maxima” and line 136 the envelope of the "minima”.
  • Line 137 represents an average of the "maxima” and “minima” and line 138 represents the function K (Max+Min-2 Med) representing the final component coming from the system and constituting the final image.
  • Max (x) formed by the "maxima" of the corresponding elements being part of vectors I i (x) when i varies (FIGS. 4, line 135);
  • Min(x) formed by the "minima" of the corresponding elements being part of vectors I i (x) when i varies (FIG. 4, line 136);
  • Med(x) formed by the "averages" of the corresponding elements being part of vectors I i (x) when i varies (FIG. 4, line 137).
  • FIG. 5 A block flow diagram of the algorithm, which, as an example, implements the operation mentioned above and shown in FIG. 3, is shown in FIG. 5.
  • the flow chart shows the complete procedure to obtain a monodimensional confocal image.
  • FIG. 6 photographs of images corresponding to the above mentioned operations, identified by a relevant legend, carried out in the presence of a real microscopic object are shown.
  • FIG. 6 is not described in further detail as deemed self-explanatory for a person skilled in the art.

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  • Physics & Mathematics (AREA)
  • General Physics & Mathematics (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Engineering & Computer Science (AREA)
  • Computer Vision & Pattern Recognition (AREA)
  • General Engineering & Computer Science (AREA)
  • Theoretical Computer Science (AREA)
  • Microscoopes, Condenser (AREA)
US08/935,298 1996-09-25 1997-09-22 Method for the acquisition of images by confocal Expired - Lifetime US6016367A (en)

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IT96FI000220A IT1286838B1 (it) 1996-09-25 1996-09-25 Metodo per la raccolta di immagini in microscopia confocale
ITFI96A0220 1996-09-25

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US6640124B2 (en) 1998-01-30 2003-10-28 The Schepens Eye Research Institute Imaging apparatus and methods for near simultaneous observation of directly scattered light and multiply scattered light
US6723290B1 (en) * 1998-03-07 2004-04-20 Levine Robert A Container for holding biologic fluid for analysis
US20100033811A1 (en) * 2006-06-16 2010-02-11 Carl Zeiss Microimaging Gmbh Autofocus device for microscopy
US20110206557A1 (en) * 2009-12-18 2011-08-25 Abbott Point Of Care, Inc. Biologic fluid analysis cartridge
WO2013144891A2 (en) 2012-03-31 2013-10-03 Cnr Consiglio Nazionale Delle Ricerche Improved confocal microscopy methods and devices
CN103674976A (zh) * 2013-11-26 2014-03-26 西安交通大学 一种用于蜂窝阵列式长细通孔的光学检测方法与系统
US8797527B2 (en) 2011-08-24 2014-08-05 Abbott Point Of Care, Inc. Biologic fluid sample analysis cartridge
US9199233B2 (en) 2010-03-31 2015-12-01 Abbott Point Of Care, Inc. Biologic fluid analysis cartridge with deflecting top panel
US9873118B2 (en) 2010-12-30 2018-01-23 Abbott Point Of Care, Inc. Biologic fluid analysis cartridge with sample handling portion and analysis chamber portion
US10132794B2 (en) 2015-09-14 2018-11-20 Essenlix Corporation Device and system for collecting and analyzing vapor condensate, particularly exhaled breath condensate, as well as method of using the same
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DE69835776T2 (de) 1997-10-29 2007-08-30 E. Calum Vancouver MacAulay Gerät und Verfahren zur Mikroskopie unter Verwendung räumlich modulierten Lichtes
US7003143B1 (en) 1999-11-02 2006-02-21 Hewitt Charles W Tomographic microscope for high resolution imaging and method of analyzing specimens
AU3267501A (en) * 1999-11-02 2001-05-14 Gary Greenberg Tomographic microscope for high resolution imaging and method of analyzing specimens
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US6640124B2 (en) 1998-01-30 2003-10-28 The Schepens Eye Research Institute Imaging apparatus and methods for near simultaneous observation of directly scattered light and multiply scattered light
US6723290B1 (en) * 1998-03-07 2004-04-20 Levine Robert A Container for holding biologic fluid for analysis
US20040156755A1 (en) * 1998-03-07 2004-08-12 Robert Levine Container for holding biologic fluid for analysis
US20100033811A1 (en) * 2006-06-16 2010-02-11 Carl Zeiss Microimaging Gmbh Autofocus device for microscopy
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DE69721167T2 (de) 2004-03-11
IT1286838B1 (it) 1998-07-17
EP0833181B1 (de) 2003-04-23
EP0833181A1 (de) 1998-04-01
ITFI960220A0 (it) 1996-09-25
ITFI960220A1 (it) 1998-03-25
DE69721167D1 (de) 2003-05-28

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